Significance Simple and affordable intervention strategies are needed to reduce the rate of HIV transmission from mother to infant in developing countries. Objectives Simian immunodeficiency virus (SIV) infection of newborn rhesus macaques is a useful animal model of human pediatric HIV infection to investigate whether short-term 9-[2-(phosphonomethoxy)-propyl]adenine (PMPA) administration can protect against perinatal infection. Results Eight newborn macaques were inoculated orally with highly virulent SIVmac within the first 3 days of age. Four of these animals were untreated controls. The other four animals were given one dose of PMPA (30 mg/kg subcutaneously) four hours before oral SIV inoculation, and were given a second and final dose of PMPA 24 hours later. All 4 untreated control animals were persistently SIV-positive within 2 weeks after virus inoculation. In contrast, no virus could be detected in the 4 animals which received 2 doses of PMPA; these animals are seronegative and healthy at 9 months of age. Future Directions Determine if 1 or 2 doses of PMPA given after virus inoculation can still protect newborn macaques against oral SIV infection. KEYWORDS PMPA, vertical transmission, primate, prophylaxis, prevention, pediatrics